PROJECT SUMMARY Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer related deaths for men in the United States. Significant progress has been made in successfully treating early stage, localized prostate cancer. However, the treatment of advanced prostate cancer continues to be a significant challenge facing the scientific and medical communities. Patients diagnosed with advanced prostate cancer commonly experience initial disease regression after undergoing treatment with androgen deprivation therapy. Yet, due to the genomic and histological heterogeneity of prostate tumors, the effectiveness of these treatments are relatively short lived, and patients progress to incurable and therapeutic resistant castration resistant prostate cancer (CRPC). Our studies aim to better understand the mechanisms that contribute to prostate cancer progression by investigating the activity of the transposable element, Long Interspersed Element-1 (LINE-1), in prostate cancer. LINE-1, also known as a ?jumping gene,? can create new insertions of itself in the genome, disrupting gene expression and genome architecture. To maintain genomic stability, LINE-1 expression is silenced in healthy somatic cells. However, recent studies have demonstrated the re- expression of LINE-1 proteins and active mobilization of LINE-1 in many cancers, including prostate cancer. New LINE-1 insertions have the potential to drive to genomic instability and tumor heterogeneity, two factors that have been shown to contribute to prostate cancer progression and the development of therapeutic resistance. Additionally, LINE-1 proteins may serve alternative functions when expressed in cancer. Yet, little is known regarding the function of LINE-1 encoded proteins in retrotransposition or their putative function in other cellular processes in prostate cancer progression. In this proposal, we will explore the effects of LINE-1 expression in prostate cancer, further investigating its possible contribution to the progression and development of therapeutic resistance. By utilizing primary prostate cancer tissue and cellular models, we will examine the role endogenous LINE-1 protein expression and LINE-1 mobilization during prostate cancer progression. The aims of this proposal are (I) assess LINE-1 expression and retrotransposition correlation with clinical outcome, (II) characterize the function of LINE-1 proteins in prostate cancer, and (III) determine the role of ORF2 phosphorylation in protein stability and degradation. Our long-term goal is to better understand the function of LINE-1 in prostate cancer in hope of developing effective therapeutic treatments for advanced CRPC.